Methods and compositions for combination immunotherapy

Abstract

Methods for generating immune responses using adenovirus vectors that allow multiple vaccinations with the same adenovirus vector and vaccinations in individuals with preexisting immunity to adenovirus are provided.

Description

CROSS-REFERENCE[0001]This application is a U.S. National Phase Application under 35 U.S.C. § 371 of International Application No. PCT / US2016 / 012496, filed Jan. 7, 2016, which claims priority to U.S. Provisional Application No. 62 / 101,969, filed Jan. 9, 2015, and U.S. Provisional Application No. 62 / 150,236, filed Apr. 20, 2015, which are incorporated herein by reference in their entirety.STATEMENT AS TO FEDERALLY SPONSORED RESEARCH[0002]This invention was made with government support under Contract No. HHSN 261200900059C, awarded by the National Cancer Institute (NCI); and Contract No. HHSN 261201100097C, awarded by the NCI; Grant No. 1R43CA134063, awarded by the NCI; Grant No. 2R44CA134063 awarded by the NCI; Grant No. 1R43CA186357 awarded by the NCI; Grant No. 1R43DE021973 awarded by the National Institute of Dental and Craniofacial Research (NIDCR); and Grant No. 2R44DE021973 awarded by the NIDCR. The government may have certain rights in the invention.RELATED APPLICATIONS[0003]Th...

AI Technical Summary

Benefits of technology

The present invention provides methods and compositions for raising an immune response against cancer-related antigens, such as MUC1, MUC1c, MUC1n, T, or CEA. The methods involve priming with a plasmid vaccine and then boosting with an adenovirus vector. The invention also describes a method of priming with a plasmid vaccine and then boosting with an adenovirus vector at different time points to enhance the immune response. The invention can be used in humans and animals, including mammals, non-human primates, rodents, rabbits, rats, mice, horses, dogs, cats, sheep, and poultry. The invention can also be used in individuals with pre-existing immunity to adenovirus. The patent text also describes the use of the invention in patients with colorectal cancer, head and neck cancer, liver cancer, breast cancer, lung cancer, bladder cancer, or pancreas cancer. The invention can be used as a standalone therapy or in combination with other therapies.

Problems solved by technology

Cancer immunotherapy achieved by delivering tumor-associated antigens (TAA) may have survival benefits; however, limitations to these strategies exist and more immunologically potent vaccines are needed.

Although, Ad5 vectors have been manufactured in large quantities and are stable for storage and delivery for outpatient administration, a major obstacle to the use of first generation (E1-deleted) Ad5-based vectors is the high frequency of pre-existing anti-Ad5 neutralizing antibodies (NAbs), which may be present in a host from prior wild type adenovirus infection or induction of Ad5 NAbs by repeated injections with Ad5-based vaccines, each resulting in inadequate immune stimulation against the target TAA.

A major problem with adenovirus (Ad) vectors has been their inability to sustain long-term transgene expression due largely to host immune responses that eliminates the Ad vector and virally-transduced cells in immune-competent subjects.

Use of first generation Ad vector vaccines is severely limited by preexisting or induced immunity of vaccines to Ad.

Although increasing vaccine doses may increase induction of desired CMI responses in Ad-immune animals, often unacceptable adverse effects result in animals and humans.

One of the major problems facing Ad5 based vectors is the high propensity of pre-existing immunity to Ads in the human population, and how this may preclude the use of conventional, Ad5 [E1-] deleted (first generation Ads) in most human populations, for any additional vaccine application.

A major obstacle to the use of first generation (E1-deleted) Ad5-based vectors is the high frequency of pre-existing anti-adenovirus type 5 neutralizing antibodies.

These antibodies can be present in a potential vaccine due to either prior wild type adenovirus infection and / or induction of adenovirus neutralizing antibodies by repeated injections with Ad5-based vaccines, each resulting in inadequate immune stimulation against the target TAA.

While cancer immunotherapy achieved by delivering tumor-associated antigens (TAA) provides survival benefits, limitations to these strategies exist and more immunologically potent vaccines are needed.

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